Bacterial lung infection is a major problem and may become life threatening for patients suffering from chronic lung disorders, such as asthma, cystic fibrosis (CF), non CF bronchiectasis and chronic obstructive pulmonary disease.
Colistin is a multicomponent polymyxin antibiotic produced by Bacillus polymyxa var. colistinus that is useful for the treatment of serious bacterial lung infections caused by gram negative bacteria, such as, for example, Pseudomonas Aeruginosa or Klebsiella pneumoniae. Polymyxin E1 and Polymyxin E2 are the major components of colistin.
When colistin is sulfomethylated, Colistimethate sodium (CMS) can be obtained. In order to become an effective antimicrobial agent, the sulfomethyl groups of CMS need to be hydrolysed thereby liberating free amino-groups. Thus, CMS is considered to be a pro-drug of colistin. The accepted consensus is that in aqueous solutions, CMS spontaneously hydrolyses and forms a complex mixture of sulfomethylated colistin derivatives and possibly colistin. It is widely accepted that a CMS drug product should not contain an amount of colistin considered to be efficacious in vivo because administration of colistin results in noted toxicities.
Coly-Mycin® M Parenteral is a drug containing CMS approved for injection. The label instructs that “parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If these conditions are observed, the product should not be used. [ . . . ] Any final intravenous infusion solution containing colistimethate sodium should be freshly prepared and used for no longer than 24 hours.”
Promixin is a drug containing CMS approved for inhalation. The label instructs that “solutions should be used immediately after reconstitution (see section 4.2). Any unused solution remaining in the nebulizer must be discarded following treatment.”
A FDA alert published in 2007 following the death of a CF patient linked to the inhalation of an aged CMS solution states that “Premixing colistimethate into an aqueous solution and storing it for longer than 24 hours results in increased concentrations of colistin in solution, increasing the potential for lung toxicity. [ . . . ] In aqueous solution, colistimethate undergoes spontaneous hydrolysis to form colistin.”
Several prior art documents try to assess the stability of CMS (Antimicrobial Agents and Chemotherapy, vol. 56, no. 12, December 2012 by Healan et al; J Phys Chem B, vol. 114, no. 14, April 2010 by Wallace et al and Antimicrobial Agents and Chemotherapy, vol. 52, no. 9, September 2008 by Wallace et al) The conclusions drawn from these studies, however, are based on detection of the final hydrolysis products only, namely, colistin A and colistin B. Such methods are not necessarily descriptive of the complex CMS compositions.
In fact, there was no available useful chromatographic method for analyzing CMS when Wallace et al and Healan et al made their studies. However, the method provided by WO 2014/195405 has made it possible to determine the quality and stability of CMS directly.
It has been discovered that an aqueous solution comprising from 80 mg A/mL to 400 mg A/mL of a sulfomethylated polymyxin exhibits physicochemical properties amenable to long-term stability, and may be utilized in the aforementioned therapeutic applications in humans.